Tazarotene (Formula I) is the international common accepted name for ethyl 6-[(4,4-dimethylthiochroman-6-yl)ethynyl]nicotinate, and has an empirical formula of C21H21NO2S and a molecular weight of 351.46. It is a synthetic retinoid used for the topical treatment of mild to moderate plaque psoriasis, acne vulgaris and photo aging.
U.S. Pat. No. 5,089,509 (the '509 patent) disclosed a process for preparation of tazarotene which includes following steps:
(a) reaction of 1-bromo-3-methyl-2-butene (formula III) with thiophenol (formula IV) to give phenyl 3-methylbut-2-enyl sulfide (formula V) followed by
(b) cyclization of phenyl 3-methylbut-2-enyl sulfide with phosphorous pentoxide and phosphoric acid to yield 4,4-dimethylthiochroman (formula VI),
(c) 4,4-dimethylthiochroman is then acetylated with acetyl chloride in the presence of stannic chloride to give 4,4-dimethyl-6-acetylthiochroman (formula VII),
(d) 4,4-dimethyl-6-acetylthiochroman is reacted with lithium diisopropylamide and diethyl chlorophosphate to give 4,4-dimethyl-6-ethynylthiochroman (formula VIII), and
(e) 4,4-dimethyl-6-ethynylthiochroman is reacted with ethyl 6-chloronicotinate (formula IX) in presence of butyl lithium, palladium tripehylphosphine and zinc chloride which resulted in formation of tazarotene (formula I). The reaction sequence is represented as per scheme-I:

US Patent application No. 2006/0106233 discloses Sonogashira coupling of 4,4-dimethyl-6-ethynylthiochroman (formula VIII) with ethyl 6-chloronicotinate (formula IX) using triethnolamine, palladium catalyst and cuprous iodide to give tazarotene which is converted to its hydrochloride salt by treatment with ethyl acetate HCl solution.
PCT application No. 2006/040644 discloses use of sulfuric acid or p-toluenesulfonic acid for cyclization of phenyl 3-methylbut-2-enyl sulfide (formula V) to give 4,4-dimethylthiochroman (formula VI). It also discloses conversion of 4,4-dimethyl-6-acetylthiochroman (formula VII) to 4,4-dimethyl-6-ethynylthiochroman (formula VIII) by sequential reaction with hydrazine and iodine.
U.S. Pat. No. 5,602,130 (the '130 patent) discloses alternative method for preparation of 4,4-dimethyl-6-ethynylthiochroman (formula VIII) by using 4-bromothiophenol (formula X) instead of thiophenol. 4-Bromothiophenol is reacted with 1-bromo-3-methyl-2-butene (formula III) and subsequently cyclized to give 6-bromo-4,4-dimethylthiochroman (formula XII). 6-Bromo-4,4-dimethylthiochroman is coupled with trimethylsilylacetylene using palladium catalyst to give 6-(trimethylsilylethynyl)-4,4-dimethylthiochroman (formula XIII) which on desilylation with a base gives 4,4-dimethyl-6-ethynylthiochroman (formula VIII). The reaction sequence is represented as per scheme-II:

U.S. Pat. No. 7,273,937 discloses the process for preparation of tazarotene, wherein 4,4-dimethyl-6-bromothiochroman (formula XII) is oxidized to the corresponding 6-bromo-4,4-dimethylthiochroman-1-oxide (formula XIV), which is reacted with 2-methyl-3-butyn-2-ol to give 4-(4,4-dimethyl-1-oxothiochroman-6-yl)-2-methylbut-3-yn-2-ol (formula XV). The compound 4-(4,4-dimethyl-1-oxothiochroman-6-yl)-2-methylbut-3-yn-2-ol is deprotected to 4,4-dimethyl-6-ethynylthiochroman-S-oxide (formula XVI). 4,4-Dimethyl-6-ethynylthiochroman-S-oxide on reaction with ethyl 6-chloronicotinate (formula IX) in presence of catalyst palladium ligand results in compound of formula XVII, which on deoxygenation yields tazarotene (Formula I). The reaction sequence is represented as per Scheme-III:

US Patent Application No. 2007/0238881 discloses preparation of tazarotene by coupling 6-chloronicotinonitrile (formula XVIII) with 4,4-dimethyl-6-ethynylthiochroman (formula VIII), subsequent hydrolysis and esterification as represented by Scheme IV.

Tazarotene is available as cream, gel and aerosol foam in the markets.
Journal article titled “The safety and efficacy of tazarotene gel, a topical acetylenic retinoid, in the treatment of psoriasis” published in Archives of dermatology, Volume: 134, Issue: 1, Pages: 57-60 states that most common adverse effect associated with tazarotene were mild to moderate burning, pruritus, stinging and erythema. In most cases erythema was manifestation of mild to moderate irritation. Adverse events associated with tazarotene resulted in cessation of treatment in about 5% of patient population.
A dimer impurity 4,4-Dimethyl-6-[4-(4,4-dimethylthiochroman-6-yl)-buta-1,3-diynyl]-thiochroman, a compound of formula (II)
also referred as the dimer impurity in present specification may be formed due to homocoupling of 4,4-dimethyl-6-ethynylthiochroman used as an intermediate during the synthesis of tazarotene. Isolation and characterization of the dimer impurity is disclosed in Journal of Pharmaceutical and Biomedical Analysis, Volume: 46 (2008), Issue 3, Pages: 574-576, titled “Impurities of tazarotene: Isolation and structural characterization”. However, the article is silent on the toxic properties of the impurity. In fact none of the literature available till date talks about the toxicity of this impurity. We have surprisingly found that this dimer impurity isis associated with side effects of tazarotene and treatment of acne or psoriasis using tazarotene substantially free of the impurity reduces the side effects.